Table 1

Details of specific interventions according to key driver diagram

Key drivers	Interventions	Outcome and process metrics
Schedule for cardiac assessment and follow-up	To avoid non-compliance due to financial constraints, diagnostic tests at baseline were planned as: T2CMR and TTE: In all patients. Holter: If the patient reported a history of syncope or palpitations. T2CMR values were classified as follows: >20 ms: No cardiac iron overload. 15–20 ms: Mild cardiac iron overload. 10–15 ms: Moderate cardiac iron overload. <10 ms: Severe cardiac iron overload. Schedule of follow-up:* Clinic visits: Monthly follow-up for initial 3 months at the primary centre. Once clinically stable, the frequency was reduced to every 2 months. Cardiac assessment: Baseline T2CMR >20 ms and normal TTE: Repeat investigations after 2 years, provided that there was optimal compliance with chelation therapy. Baseline T2CMR <20 ms and normal TTE: T2CMR and TTE repeated yearly. Baseline T2CMR <20 ms and TTE abnormal‡: T2*CMR repeated yearly and TTE repeated after 6 months of intensive chelation therapy.	Process metric Adequacy of cardiac assessment and follow-up according to guidelines. Outcome metric† Percentage of patients with increase or stabilisation of T2CMR value after intervention. Increase in the cumulative median T2CMR of the patient cohort. Percentage of patients with improvement in cardiac dysfunction on echocardiography.
Optimisation of chelation protocol	Dose and combination of chelation therapy § was defined as follows: ‘Standard’ dose: Prescribed in the absence of cardiac iron overload. Defined as DFO prescribed at 40 mg/kg/day at least 5 days a week, DFP at 75 mg/kg/day (daily) and DFX at 30 mg/kg/day (daily). ‘Cardiac’ dose: Prescribed in the presence of cardiac iron overload. Defined as DFO prescribed at 50–60 mg/kg/day (at least 5 days a week), DFP at 100 mg/kg/day and DFX at 40 mg/kg/day. Dual therapy: Two chelation drugs were prescribed. This includes combination of DFO–DFP, DFO–DFX or DFP–DFX. Monotherapy: Single chelation drug was prescribed. Emergent chelation: 24-hour DFO infusion (cardiac dose) for at least 1 month along with a second or in some cases, a third chelating agent (at cardiac doses). Following protocol was implemented after agreement of stakeholders at both centres: Abnormal TTE±normal holter: T2CMR >20 ms: Single chelating agent (standard dose).¶ T2CMR 10–20 ms: Dual chelating agents (cardiac dose).¶ T2CMR <10 ms: Emergent chelation with dual chelating agents (cardiac dose).¶ Normal TTE±holter: T2CMR >20 ms: Single chelating agent (standard dose). T2CMR 10–20 ms: Single chelating agent (cardiac dose). T2CMR <10 ms: Dual chelating agents (cardiac dose).	Process metric Standardisation of chelation therapy.
Enforcement of compliance with chelation therapy	Compliance check of chelation therapy: Since there were no drug levels to assess compliance with chelation therapy, a detailed medication history by the haematologist was performed at every follow-up visit. Compliance was described as follows: Optimal compliance: When chelation drugs were taken as prescribed with drug missed for not more than 7 days between each 2-monthly follow-up. Partial compliance: When chelation drug was missed for >7 but<15 days between the 2-monthly follow-ups or taking 50% dose of monotherapy prescribed or taking one drug in the prescribed combination therapy. Non-compliance: When drug gap exceeded 15 days and/or not on any chelation therapy. Other strategies: Awareness: Patients and families were educated about benefits of optimal chelation therapy during clinic visits. Availability of drugs: Drugs were made available at the participating thalassaemia centres or by referral to other thalassaemia centres and/or government hospitals where chelation medications were offered free of cost. Standardisation of chelation drug AE severity description and its management: A novel chelation medication AE severity description was developed and categorised into five severity levels to standardise drug continuation/discontinuation/change by both patients and healthcare professionals (details in table 2).	Process metric Compliance with recommended chelation therapy. Reporting of AE severity levels. Percentage of patients with inappropriate discontinuation or continuation of chelation therapy after introduction of AE severity description. Percentage of severity level 3–5 AE on intensification therapy.

*T2*CMR was not performed in patients presenting with acute heart failure requiring emergent admission in hospital as breath holding for MRI was not possible in these patients. T2*CMR was obtained once patient was stabilised with emergent chelation for at least 2 weeks.
†Outcome metric was meant to measure the effectiveness of the complete initiative thus demonstrating the cumulative effect of all the key drivers.
‡Abnormal TTE is defined as systolic (left ventricular ejection fraction <56% and/or age based low peak systolic left ventricular global longitudinal strain value) and/or diastolic dysfunction.
§In the absence of iron overload or out of proportion cardiac dysfunction not explained by iron load, evaluate for other causes of myocardial dysfunction that is, viral (hepatitis B and C, HIV etc) myocarditis, electrolyte (eg, profound hypocalcaemia) or vitamin (eg, Vitamin D or B deficiency etc), endocrinological (eg, hypothyroidism, hypocalcaemia etc) related cardiac dysfunction.
¶DFO was infused daily by a subcutaneous infusion pump for 8–12 hours or in hospital over 24 hours (if patient had signs of heart failure or significant cardiac dysfunction on TTE with moderate to severe cardiac siderosis on T2*CMR), DFP was prescribed daily in three divided doses and DFX was given in a one time per day dosing schedule. All oral chelators were prescribed after meals.
AE, adverse event; DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox; T2*CMR, cardiac T2* magnetic resonance imaging; TTE, transthoracic echocardiography.